Gliomas are the most common primary brain tumors ranging from benign low- grade astrocytomas to highly malignant glioblastoma multiforme. The classification of primary glial tumors reflecting their biological aggressiveness is based upon histopathologic characteristics. We have taken several approaches to understand and identify, at a molecular level, the underlying mechanisms that translate into the extremely malignant behavior of glioblastoma. 1. We have used X-chromosome inactivation analysis to study the clonal composition of glioblastomas, which were found to be monoclonal. 2. The genomic organization and expression of PDGFRs and EGFR were analyzed in 50 glial tumors. Alpha-PDGFR and EGFR were amplified, whereas alpha- and beta-PDGFR and EGFR were overexpressed in distinct subsets of glial tumors. 3. The transcription of bGFG, its surface-associated receptor, flg, TGF alpha, and TGF beta, was generally elevated in most of the glioblastoma cell lines tested. 4. Recessive mutations that predispose to cancer are unmasked in several human cancers by the loss of normal alleles. Restriction fragment length polymorphism analysis (RFLP) was used to compare the constitutional and tumor genotypes in a panel of 40 glioblastomas. Loss of heterozygosity of several markers on chromosomes 17 and 10 was detected in a significant number of glioblastoma multiforme. The p53 gene was deleted and/or mutated in 75% of the tumors with gene losses on chromosome 17. Deletion mapping studies on chromosome 17 suggested the presence of another potential tumor suppressor gene distinct from the p53 gene. 5. Six matched pairs of primary and recurrent tumors were analyzed for allelic deletions of chromosomes 10 and 17. The data clearly demonstrated additional genetic abnormalities in recurrent tumors.